(Aryl(alkyl)carbonyl)-heterocyclic compounds and their use in the treatment of anxiety and depression

ABSTRACT

The invention relates to a compound selected from those of formula (I): ##STR1## wherein Ar, n, B and A are as defined in the description, to their optical isomers, and to their addition salts there of with a pharmaceutically-acceptable acid or base. The compounds are useful for treating or preventing anxiety and depression.

The present application is division of our prior-filed application Ser. No. 08/206,451, filed Mar. 4, 1994, now U.S. Pat. No. 5,387,586.

The present invention relates to new (aryl(alkyl)carbonyl)-heterocyclic compounds, to processes for preparing them and to pharmaceutical compositions containing them.

It is known that 5-HT₂ serotoninergic receptors are associated with an improvement in schizophrenic conditions. They have also shown beneficial effects in anxiety and depression.

Compounds having a good affinity for these 5-HT₂ receptors would therefore be useful in the clinical situation for the treatment of these pathologies.

The Applicant has discovered new (aryl(alkyl)carbonyl)-heterocyclic compounds which have a high affinity for 5-HT₂ receptors, some of these compounds also surprisingly having an analgesic activity.

Heterocyclic compounds, described as having an affinity for melatoninergic receptors, are known from the state of the art (Patent Application EP 506539) but these compounds do not have any comparable affinity for 5-HT₂ receptors nor do they have any analgesic activity.

More particularly, the invention relates to the compounds of formula (I): ##STR2## in which: Ar: represents a phenyl or naphthyl group, Ar being unsubstituted or substituted by one or more radicals chosen from halogen, lower alkyl, lower alkoxy and trifluoromethyl,

n: represents 0 or an integer from 1 to 4,

B: represents a ##STR3## group, and, A: represents a group of formula (A1) or (A2): ##STR4## in which E: represents a linear or branched alkylene chain containing 1 to 6 carbon atoms,

R₁ : represents a radical chosen from hydrogen, hydroxyl, lower alkyl and lower alkoxy,

R₂ : represents a radical chosen from hydrogen, lower alkyl and ##STR5## where E₁ has the same definition as E as described above and where R₄ and R₅ are chosen, independently from one another, from hydrogen and lower alkyl, or form, together with the nitrogen atom which carries them, a heterocycle chosen from pyrrolidine, piperidine, substituted piperidine, morpholine, piperazine and substituted piperazine,

R₃ : represents a radical chosen from hydrogen and lower alkyl, and

X: represents a sulfur or oxygen atom, to their optical isomers,

and to their addition salts with a pharmaceutically acceptable base or acid,

it being understood that, except when otherwise specified, the terms "lower alkyl" and "lower alkoxy" denote linear or branched groups containing 1 to 6 carbon atoms, and the term "substituted" assumed by the "piperidine" and "piperazine" heterocycles means that these heterocycles can be substituted in the 4-position by a radical chosen from lower alkyl, aryl and lower arylalkyl, the term "aryl" denoting a phenyl, naphthyl or pyridyl group which can itself be unsubstituted or substituted by one or more radicals chosen from halogen, lower alkyl, hydroxyl, lower alkoxy and trifluoromethyl.

Mention may be made, among pharmaceutically acceptable acids which can be used to form an addition salt with the compounds of the invention, by way of examples and in a non-limiting way, of hydrochloric, sulfuric, phosphoric, tartaric, malic, maleic, fumaric, oxalic, methanesulfonic, ethanesulfonic, camphoric and citric acids.

Mention may be made, among pharmaceutically acceptable bases which can be used to salify the compounds used according to the invention, by way of examples and in a non-limiting way, of sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, ethanolamine, arginine, lysine and diethanolamine.

The invention applies to the process for the preparation of the compounds of formula (I), wherein a compound of formula (II): ##STR6## in which Ar, n and B are as defined in the formula (I), is reacted with a compound of formula (III/A1): ##STR7## or of formula (III/A2): ##STR8## in which E, X, R₁, R₂ and R₃ are as defined in the formula (I) and Hal represents a halogen atom, in order to obtain the corresponding compound of formula (I),

the compounds of formula (I) being, if appropriate:

purified according to one or more purification methods chosen from crystallization, chromatography on a silica column, extraction, filtration and passing through charcoal or resin,

separated, in the pure form or in the form of mixtures, into their optical isomers,

and salified with a pharmaceutically acceptable acid or base.

The invention also applies to the process for obtaining compounds of formula (I/a): ##STR9## in which Ar, n, B, E, X, R₁ and R₂ are as defined in the formula (I), wherein a compound of formula (IV): ##STR10## in which Ar, n, B and E are as defined above and Hal' represents a halogen atom, is reacted with a compound of formula (7): ##STR11## in which X, R₁ and R₂ are as described above, in order to obtain the corresponding compounds of formula (I/a),

the compounds of formula (I/a) being, if appropriate:

purified according to one or more purification methods chosen from crystallization, chromatography on a silica column, extraction, filtration, and passing through charcoal or resin,

separated, in the pure form or in the form of mixtures, into their optical isomers,

and salified with a pharmaceutically-acceptable acid or base.

The starting materials used in the processes described above are either commercially available or easily accessible to those skilled in the art according to processes known from the literature or proposed during the preparation examples described below.

The compounds of formula (II) are, for example, easily accessible to those skilled in the art by reacting a compound of formula (II/a): ##STR12## in which B is as described in formula (I) and R₆ represents a hydrogen atom or a protecting group of the nitrogen,

with a compound of formula (II/b):

    Ar                                                         (II/b)

in which Ar is as defined in the formula (I), or with a compound of formula (II/c):

    Ar--(CH.sub.2).sub.n --MgBr                                (II/c)

in which Ar and n are as defined in the formula (I), in order to obtain, if appropriate after removal of the protecting group R₆, the corresponding compounds of formula (II).

The compounds of formula (IV) are also easily obtained by reacting a compound of formula (II): ##STR13## in which Ar, n and B are as defined in the formula (I), with an alcohol of formula (VI):

    Hal'--E--OH                                                (VI)

in which E is as defined in the formula (I) and Hal' represents a halogen atom, in order to obtain the corresponding compound of formula (IV).

The compounds of formula (III/A1) and (III/A2) are easily accessible so those skilled in the art according to processes analogous to those described in Application EP 506539.

The Applicant has discovered that the compounds of the invention had a remarkable affinity for 5-HT₂ serotoninergic receptors.

This very significant binding ability is revealed in Example A of the present document (Example A: Measurement of the affinity for serotoninergic receptors).

This high affinity for 5-HT₂ receptors shown by the compounds of the invention turns out to be surprising since the compounds of the prior art mentioned in Application EP 506539 do not in the least show such an affinity for these receptors.

The antipsychotic activity of the compounds of the invention was shown by the test of antagonism of amphetamine-induced hyperactivity (Example B of the present application: Study of antagonism of amphetamine-induced hyperactivity).

The compounds of the invention also have an anxiolytic activity (Example C: Light-dark cage test).

The equally surprising analgesic activity of the compounds of the invention is shown in Example D (hotplate test).

The compounds of the invention, by their method of action, are therefore new candidates for the treatment and prevention of pathologies which require psychotropic agents, and the treatment of conditions involving pain.

The compounds of the invention are more particularly useful in the treatment and prevention of anxiety, depression and depressive syndromes, psychotic conditions and Parkinson's disease and the treatment of pain.

Another subject of the present invention is pharmaceutical compositions containing, as active principle, one or more compounds of formula (I), or their addition salts with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients, vehicles or diluents.

Mention can be made, among pharmaceutical compositions according to the invention, by way of examples and in a non-limiting way, of those which are suitable for oral, parental, nasal, rectal, perlingual, ocular or pulmonary administration and especially injectable preparations, aerosols, eye- or nosedrops, simple, film-coated or sugar-coated tablets, capsules, including gelatin capsules, suppositories, creams, ointments and dermal gels.

The useful dose varies according to the age and weight of the patient, the administration route, the nature of the ailment and possible associated treatments and ranges between 0.05 mg and 50 mg per 24 hours taken once or twice.

EXAMPLE 1 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE ##STR14## STAGE A: 1-(2-CHLOROETHYL)-4-(4-FLUOROBENZOYL)PIPERIDINE

1-acetylpiperidine-4-carboxylic acid 1-Acetylpiperidine-4-carboxylic acid is prepared by bringing a solution of piperidine-4-carboxylic acid in acetic anhydride to reflux for 2 hours and then stirring for 16 hours at room temperature. The solution is then concentrated and the residue is triturated in ether. The solid compound is recovered by filtration.

Recrystallization solvent: isopropanol/isopropyl ether

Melting point: 180°-182° C.

1-acetyl-4-(4-fluorobenzoyl)piperidine 1-Acetylpiperidine-4-carboxylic acid is poured into a thionyl chloride solution. The acyl chloride formed precipitates from solution. The solid is dried after washing several times with petroleum ether. The infrared spectrum shows complete conversion of the acid to the acyl chloride. The acyl chloride is slowly added to aluminum chloride in solution in fluorobenzene, with stirring. The mixture is then brought to reflux for 1 hour. The mixture is poured onto ice and the two resulting phases are separated. The aqueous phase is extracted twice with chloroform and the extracts are added to the fluorobenzene separated previously. The organic solution is dried (Na₂ SO₄) and filtered. The filtrate is concentrated under reduced pressure and a crystalline white solid is obtained.

Melting point: 75°-78° C.

4-(4-fluorobenzoyl)piperidine

A solution of 1-acetyl-4-(4-fluorobenzoyl)piperidine in 6N hydrochloric acid is brought to reflux for 2 hours. The solution is cooled and then extracted twice with ether. The aqueous solution is made basic (NaOH) and then extracted with benzene. The extracts are dried (Na₂ SO₄) and filtered. The filtrate is concentrated under reduced pressure and the residual oil is converted to a hydrochloric acid salt.

Melting point (hydrochloride): 222°-224° C.

1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine 0.01 mol of the hydrochloride of 4-(4-fluorobenzoyl)piperidine in an ethanolic sodium hydroxide solution is introduced into a 250 cm³ round-bottomed flask equipped with a water-cooled reflux condenser. The reaction mixture is brought to reflux and 0.012 mol of 2-bromoethanol is added. Reflux is maintained for 2 hours, the mixture is allowed to cool, the inorganic precipitate formed is filtered off and the alcohol is evaporated under reduced pressure.

The residue is taken up in 75 cm³ of anhydrous chloroform, the mixture is cooled in an ice bath, 0.04 mol of thionyl chloride is added, a water-cooled reflux condenser is fitted and the reaction is continued for four hours at reflux of the solvent. The mixture is allowed to cool, the chloroform is evaporated and then the residue is taken up in absolute alcohol and brought to boiling point in order to remove the thionyl chloride.

The absolute alcohol is evaporated and an anhydrous acetone solution saturated with gaseous hydrochloric acid is added to the residue. The precipitate obtained is filtered off and then recrystallized.

Melting point (hydrochloride): 110°-112° C.

Yield: 65%

Recrystallization solvent: anhydrous acetone

    ______________________________________                                         Elemental analysis:                                                            Calculated:  C % 52.27  H % 6.14  N % 4.38                                     Found:       C % 52.68  H % 6.18  N % 4.41                                     Infrared spectrometry:                                                         3000-2600 cm.sup.-1                                                                      v CH (alkyls)                                                        1670 cm.sup.-1                                                                           v CO                                                                 1610-1580 cm.sup.-1                                                                      v C═C (aromatics)                                                ______________________________________                                    

STAGE B:

3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE

0.01 mol of benzothiazolin-2-one is dissolved in dimethylformamide in a 250 cm³ ground-neck flask equipped with a water-cooled reflux condenser. 0.06 mol of potassium carbonate is added and the mixture is brought to reflux. The mixture is left stirring for 30 minutes and 0.012 mol of the hydrochloride of 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine, dissolved beforehand in dimethylformamide, is added. Stirring is continued for one hour, the mixture is allowed to cool, the inorganic insoluble material is filtered off and the filtrate is poured onto crushed ice.

The precipitate obtained is filtered off, dried, dissolved in anhydrous acetone and then the hydrochloride is precipitated by sparging with a stream of dry gaseous hydrochloric acid. The product obtained is filtered off, dried and then recrystallized.

Melting point (hydrochloride): 254°-256° C.

Yield: 67%

Recrystallization solvent: anhydrous acetone

Basic nitrogen assay: for one basic nitrogen

Basic nitrogen percentage, theory: 3.33%

Basic nitrogen percentage, found: 3.61%

    ______________________________________                                         Elemental analysis: (title compound + 7/2 H.sub.2 O)                           Calculated:  C % 52.18  H % 5.16  N % 5.95                                     Found:       C % 52.11  H % 5.55  N % 5.78                                     Infrared spectrometry:                                                         3100-2800 cm.sup.-1                                                                      v CH (alkyls)                                                        2700-2300 cm.sup.-1                                                                      v NH+                                                                1610 cm.sup.-1                                                                           v CO (NCOS + ketones)                                                1580 cm.sup.-1                                                                           v C═C                                                            ______________________________________                                    

EXAMPLE 2 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZINYL]BUTYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one with the dihydrochloride of 6-{4-[4-(3-trifluoromethylphenyl)piperazinyl]butyl}benzothiazolin-2-one.

Melting point (trihydrochloride): 250°-252° C.

Yield: 37%

Recrystallization solvent: absolute alcohol

Basic nitrogen assay: for three basic nitrogens

Basic nitrogen percentage, theory: 5.39%

Basic nitrogen percentage, found: 5.31%

    ______________________________________                                         Infrared spectrometry:                                                         ______________________________________                                         3080-2840 cm.sup.-1                                                                             v CH (alkyls)                                                 2500-2000 cm.sup.-1                                                                             v NH+                                                         1670 cm.sup.-1   v CO (NCOS + ketones)                                         1580 cm.sup.-1   v C═C (aromatics)                                         ______________________________________                                    

EXAMPLE 3 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(4-[4-(2-METHOXY-PHENYL)PIPERAZINYL]BUTYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one with the dihydrochloride of 6-{4-[4-(2-methoxyphenyl)piperazinyl]butyl}benzothiazolin-2-one.

Melting point (trihydrochloride): 252°-254° C.

Yield: 30%

Recrystallization solvent: absolute alcohol

Basic nitrogen assay: for three basic nitrogens

Basic nitrogen percentage, theory: 5.67%

Basic nitrogen percentage, found: 5.86%

    ______________________________________                                         Elemental analysis: (title compound + 3H.sub.2 O)                              Calculated:  C % 51.60  H % 5.15  N % 6.97                                     Found:       C % 51.93  H % 5.37  N % 6.73                                     Infrared spectrometry:                                                         3100-2800 cm.sup.-1                                                                      v CH (alkyls)                                                        2700-2300 cm.sup.-1                                                                      v NH+                                                                1670 cm.sup.-1                                                                           v CO (NCOS + ketone)                                                 1590 cm.sup.-1                                                                           v C═C (aromatics)                                                1020 cm.sup.-1                                                                           v OCH.sub.3                                                          ______________________________________                                    

EXAMPLE 4

3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE ##STR15##

The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one with the dihydrochloride of 6-(4-morpholinobutyl)benzothiazolin-2-one.

Melting point (dihydrochloride): 258°-260° C.

EXAMPLES 5 TO 22

By carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one in Stage B with:

6-(2-morpholinoethyl)benzothiazolin-2-one, there is obtained:

EXAMPLE 5 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(2-MORPHOLINOETHYL)BENZOTHIAZOLIN-2-ONE

6-[2-(4-phenylpiperazinyl)ethyl]benzothiazolin-2-one, there is obtained:

EXAMPLE 6 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[2-(4-PHENYLPIPERAZINYL)ETHYL]BENZOTHIAZOLIN-2-ONE

6-{2-[4-(3-trifluoromethylphenyl)piperazinyl]ethyl}benzothiazolin-2-one, there is obtained:

EXAMPLE 7 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-ONE

6-(N,N-dipropylaminoethyl)benzothiazolin-2-one, there is obtained:

EXAMPLE 8 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(N,N-DI-PROPYLAMINOETHYL)BENZOTHIAZOLIN-2-ONE

6-{2-[4-(2,3,4-trimethoxyphenylmethyl)piperazinyl]ethyl}benzothiazolin-2-one, there is obtained:

EXAMPLE 9 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(2,3,4-TRIMETHOXYPHENYLMETHYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-ONE

6-methoxybenzothiazolin-2-one, there is obtained:

EXAMPLE 10 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-METHOXYBENZOTHIAZOLIN-2-ONE

6-hydroxybenzothiazolin-2-one, there is obtained:

EXAMPLE 11 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL)-6-HYDROXYBENZOTHIAZOLIN-2-ONE

5-methoxybenzothiazolin-2-one, there is obtained:

EXAMPLE 12 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-5-METHOXYBENZOTHIAZOLIN-2-ONE

Melting point: 248°-250° C.

6-(N,N-dipropylaminoethyl)-5-methoxybenzothiazolin-2-one, there is obtained:

EXAMPLE 13 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(N,N-DIPROPYLAMINOETHYL)-5-METHOXYBENZOTHIAZOLIN-2-one

6-{2-[4-(3-pyridyl)piperazinyl]ethyl}benzothiazolin-2-one, there is obtained:

EXAMPLE 14 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(3-PYRIDYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-ONE

6-{4-[4-(2-methylphenyl)piperazinyl]butyl}benzothiazolin-2-one, there is obtained:

EXAMPLE 15 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(2-METHYLPHENYL)PIPERAZINYL]BUTYL}BENZOTHIAZOLIN-2-ONE

5-methoxy-6-(4-morpholinobutyl)benzothiazolin-2-one, there obtained:

EXAMPLE 16 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-5-METHOXY-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE

6-[4-(4-naphthylpiperazinyl)butyl]benzothiazolin-2-one, there is obtained:

EXAMPLE 17 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[4-(4-NAPHTHYLPIPERAZINYL)BUTYL]BENZOTHIAZOLIN-2-ONE

6-{4-[4-(4-methoxynaphthyl)piperazinyl]butyl}benzothiazolin-2-one, there is obtained:

EXAMPLE 18 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(4-METHOXYNAPHTHYL)PIPERAZINYL]BUTYL}BENZOTHIAZOLIN-2-ONE

6-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}benzothiazolin-2-one, there is obtained:

EXAMPLE 19 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{2-[4-(2-METHOXYPHENYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-ONE

6-[2-(4-phenylpiperidino)ethyl]benzothiazolin-2-one, there is obtained:

EXAMPLE 20 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[2-(4-PHENYLPIPERIDINO)ETHYL]BENZOTHIAZOLIN-2-ONE

6-[3-(4-phenylpiperazin-1-yl)propyl]benzothiazolin-2-one, there is obtained:

EXAMPLE 21 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[3-(4-PHENYLPIPERAZINYL)PROPYL]BENZOTHIAZOLIN-2-ONE

6-[4-(4-phenylpiperazin-1-yl)butyl]benzothiazolin-2-one, there is obtained:

EXAMPLE 22 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-[4-(4-PHENYLPIPERAZINYL)BUTYL]BENZOTHIAZOLIN-2-ONE EXAMPLE 23 3-{2-[4-(3,4-DIMETHOXYBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but starting from 4-(3,4-dimethoxybenzoyl)piperidine in place of 4-(4-fluorobenzoyl)piperidine.

EXAMPLE 24 3-{2-[4-(4-METHOXYBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but starting from 4-(4-methoxybenzoyl)piperidine in place of 4-(4-fluorobenzoyl)piperidine.

EXAMPLE 25 3-[2-(4-BENZOYLPIPERIDINO)ETHYL]BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but starting from 4-benzoylpiperidine in place of 4-(4-fluorobenzoyl)piperidine.

EXAMPLES 26 AND 27

The compounds of the following examples are obtained by carrying out the reaction as in Example 1 but using the appropriately substituted piperidines in place of 4-(4-fluorobenzoyl)piperidine.

EXAMPLE 26 3-{2-[4-(3,4-DICHLOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 27 3-{2-[4-(4-TRIFLUOROMETHYLBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE EXAMPLES 28 TO 41

The compounds of the following examples are obtained by carrying out the reaction as in Example 4 but replacing 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines:

EXAMPLE 28 3-{2-[4-(4-METHOXYBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 29 3-{2-[4-(4-TRIFLUOROMETHYLBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 30 3-{2-[4-(3,4-DICHLOROBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 31 3-[2-(4-BENZOYLPIPERIDINO)ETHYL]-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 32 3-{2-[4-(3,5-DIBROMO-2,6-DIMETHOXYBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 33 3-{2-[4-(4-CHLOROBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 34 3-{2-[4-(3-PHENYLPROPIONYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 35 3-{2-[4-(5-PHENYLVALERYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 36 3-{2 -{4-[4-(4-FLUOROPHENYL)BUTYRYL]PIPERIDINO}-ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 37 3-{3-[4-(4-FLUOROBENZOYL)PIPERIDINO]-2-METHYLPROPYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 38 3-{2-[4-(6-FLUORONAPHTHYLCARBONYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 39 3-{2-[4-(NAPHTHYLCARBONYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 40 3-{2-[4-(7-METHOXYNAPHTHYLCARBONYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 41 3-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO}BUTYL}-6-(4-MORPHOLINOBUTYL)BENZOTHIAZOLIN-2-ONE EXAMPLE 42 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{3-[4-(2-METHOXYPHENYL)PIPERAZINYL]-2-METHYLPROPYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one with 6-{3-[4-(2-methoxyphenyl)piperazinyl]-2-piperazinyl]-2-methylpropyl}benzothiazolin-2-one.

EXAMPLE 43 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOXAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but replacing benzothiazolin-2-one with benzoxazolin-2-one.

EXAMPLE 44 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(3-TRIFLUOROMETHYLPHENYL)PIPERAZINYL]BUTYL}BENZOXAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but replacing 6-{4-[4-(3-trifluoromethylphenyl)piperazinyl]butyl}-benzothiazolin-2-one with 6-{4-[4-(3-trifluoromethylphenyl)piperazinyl]butyl}benzoxazolin-2-one.

EXAMPLE 45 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-{4-[4-(2-METHOXYPHENYL)PIPERAZINYL]BUTYL}BENZOXAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 3 but replacing 6-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}benzothiazolin-2-one with 6-{4-4-(2-methoxyphenyl)piperazin-1-yl]butyl}benzoxazolin-2-one.

EXAMPLE 46 3-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}-6-(4-MORPHOLINOBUTYL)BENZOXAZOLIN-2-ONE

The title compond is obtained by carrying out the reaction as in Example 4 but replacing 6-(4-morpholinobutyl)benzothiazolin-2-one with 6-(4-morpholinobutyl)benzoxazolin-2-one.

EXAMPLE 47 3-{2-[4-(4-FLUOROBENZOYL)PIPERAZINYL]ETHYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 1 but starting, in Stage A, from piperazine-1-carboxylic acid in place of piperidine-4-carboxylic acid.

EXAMPLE 48 3-METHYL-6-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE ##STR16## STAGE A: 3-METHYL-6-(2-BROMOETHYL)BENZOTHIAZOLIN-2-ONE

0.15 mol of 3-methyl-6-bromoacetylbenzothiazolin-2-one (42.9 g) is dissolved in 1 mol of trifluoroacetic acid (77 cm³) in a 250 cm³ ground-neck flask. 0.33 mol of triethylsilane (52.70 cm³) is introduced dropwise using a dropping funnel, with magnetic stirring. A calcium chloride drying tube is fitted and stirring is maintained for the required time at room temperature. The reaction mixture is poured into 500 cm³ of ice-cold water. The precipitate obtained is filtered off, washed with water until the wash liquors are neutral, dried and then recrystallized.

Reaction time: 20 hours

Melting point: 97°-98° C.

Yield: 86%

Recrystallization solvent: cyclohexane

    ______________________________________                                         Elemental analysis:                                                            Calculated:  C % 44.13  H % 3.70  N % 5.15                                     Found:       C % 44.26  H % 3.60  N % 5.34                                     Infrared spectrometry:                                                         3050-2850 cm.sup.-1                                                                      v CH (alkyls)                                                        1660 cm.sup.-1                                                                           v CO (NCOS)                                                          1610-1580 cm.sup.-1                                                                      v C═C (aromatics)                                                ______________________________________                                    

STAGE B:

3-METHYL-6-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE

0.01 mol of 3-methyl-6-(2-bromoethyl)benzothiazolin-2-one is dissolved in 50 cm³ of anhydrous acetone. The acetone is heated to reflux. 0.022 mol of triethylamine in solution in 20 cm³ of anhydrous acetone is added and then 0.01 mol of the hydrochloride of 4-(4-fluorobenzoyl)piperidine is added with magnetic stirring. Heating is continued for 24 hours and then the triethylamine hydrobromide formed is filtered off.

The filtrate is evaporated and the residue is taken up in 50 cm³ of a 1M HCl solution. The expected product precipitates, is filtered off, is dried and is then recrystallized.

Melting point (hydrochloride): 224°-226° C.

Yield: 62%

Recrystallization solvent: absolute alcohol

Basic nitrogen assay: for one basic nitrogen

Basic nitrogen percentage, theory: 3.22%

Basic nitrogen percentage, found: 2.94%

    ______________________________________                                         Infrared spectrometry:                                                         ______________________________________                                         3000-2800 cm.sup.-1                                                                             v CH (alkyls)                                                 2600-2400 cm.sup.-1                                                                             v NH                                                          1660 cm.sup.-1   v CO (NCOS)                                                   1660 cm.sup.-1   v CO (ketone)                                                 1600-1580 cm.sup.-1                                                                             v C═C (aromatics)                                         ______________________________________                                    

EXAMPLE 49 3-METHYL-6-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO]BUTYL}BENZOTHIAZOLIN-2-ONE

The title product is obtained by carrying out the reaction as in Example 48 but replacing, in Stage A, 3-methyl-6-bromoacetylbenzothiazolin-2-one with 3-methyl-6-bromobutyrylbenzothiazolin-2-one.

EXAMPLES 50 TO 52

The compounds of the following examples are obtained by carrying out the reaction as in Example 48 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines:

EXAMPLE 50 3-METHYL-6-{4-[4-(4-CHLOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 51 3-METHYL-6-[4-(4-BENZOYLPIPERIDINO)ETHYL]BENZOTHIAZOLIN-2-ONE EXAMPLE 52 3-METHYL-6-{4-[4-(4-METHOXYBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 53 3-METHYL-6-{2-[4-(4-METHOXYBENZOYL)PIPERIDINO]ETHYL}BENZOXAZOLIN-2-ONE

The title product is obtained by carrying out the reaction as in Example 48 but replacing, in Stage A, 3-methyl-6-bromoacetylbenzothiazolin-2-one with 3-methyl-6-bromoacetylbenzoxazolin-2-one.

EXAMPLE 54 6-{2-[4-(4-FLUOROBENZOYL)PIPERIDINO]ETHYL}BENZOTHIAZOLIN-2-ONE

The title compound is obtained by carrying out the reaction as in Example 48 but replacing 3-methyl-6-bromoacetylbenzothiazolin-2-one with 6-bromoacetylbenzothiazolin-2-one.

EXAMPLE 55 6-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO]BUTYL}BENZOTHIAZOLIN-2-ONE

The title product is obtained by carrying out the reaction as in Example 48 but replacing, in Stage A, 3-methyl-6-bromoacetylbenzothiazolin-2-one with 6-bromobutyrylbenzothiazolin-2-one.

EXAMPLES 56 TO 58

The compounds of the following examples are obtained by carrying out the reaction as in Example 55 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines:

EXAMPLE 56 6-{4-[4-(4-CHLOROBENZOYL)PIPERIDINO]BUTYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 57 6-[4-(4-BENZOYLPIPERIDINO)BUTYL]BENZOTHIAZOLIN-2-ONE EXAMPLE 58 6-{4-[4-(4-METHOXYBENZOYL)PIPERIDINO]BUTYL}BENZOTHIAZOLIN-2-ONE EXAMPLE 59 3-METHYL-6-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE

The title product is obtained by carrying out the reaction as in Example 48 but replacing 3-methyl-6-bromoacetylbenzothiazolin-2-one with 3-methyl-6-bromobutyrylbenzoxazolin-2-one.

EXAMPLES 60 TO 62

The compounds of the following examples are obtained by carrying out the reaction as in Example 59 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperdine with the appropriately substituted piperidines:

EXAMPLE 60 3-METHYL-6-{4-[4-(4-CHLOROBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE EXAMPLE 61 3-METHYL-6-[4-(4-BENZOYLPIPERIDINO)BUTYL]BENZOXAZOLIN-2-ONE EXAMPLE 62 3-METHYL-6-{4-[4-(4-METHOXYBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE EXAMPLE 63 6-{4-[4-(4-FLUOROBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE

The title product is obtained by carrying out the reaction as in Example 48, but replacing 3-methyl-6-bromoacetylbenzothiazolin-2-one with 6-bromobutyrylbenzoxazolin-2-one.

EXAMPLES 64 TO 66

The compounds of the following examples are obtained by carrying out the reaction as in Example 63 but replacing, in Stage B, 4-(4-fluorobenzoyl)piperidine with the appropriately substituted piperidines:

EXAMPLE 64 6-{4-[4-(4-CHLOROBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE EXAMPLE 65 6-[4-(4-BENZOYLPIPERIDINO)BUTYL]BENZOXAZOLIN-2-ONE EXAMPLE 66 6-{8-[4-(4-METHOXYBENZOYL)PIPERIDINO]BUTYL}BENZOXAZOLIN-2-ONE EXAMPLE A Measurement of the Affinity for Serotoninergic Receptors

PROTOCOL:

The in-vitro affinity of the compounds of the invention was determined

for 5-HT_(1A) serotoninergic receptors, by measuring the displacement of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), on rat hippocampus preparations,

for 5-HT_(1C) serotoninergic receptors, by measuring the displacement of N-methylmesulergine, on rat frontal cortex and hippocampus preparations,

for 5-HT_(1D) serotoninergic receptors, by measuring the displacement of 5-hydroxytryptamine, on rat cortex, striatum and globus pallidus preparations,

for 5-HT₂ serotoninergic receptors, by measuring the displacement of aminoiodoketanserin, on rat frontal cortex preparations,

for 5-HT₃ serotoninergic receptors, by measuring the displacement of BRL 43694, on rat area postrema preparations.

RESULTS:

The compounds of the invention show a very high affinity for 5-HT₂ serotoninergic receptors. As examples, the compounds of Examples 1 and 3 have an IC₅₀ (concentration inhibiting binding of the labelled ligand by 50% of the order of 10-⁹ M to ¹⁰⁻¹⁰ M (compounds of Examples 1 and 3: IC₅₀ : 10-⁹ M, compound of Example 4: 5.10-¹⁰ M).

The compounds of the invention also show a significant binding selectivity for 5-HT₂ receptors with respect to other serotoninergic receptors.

The compounds of Application EP 506539 do not in the least show such an affinity and selectivity for 5-HT₂ receptors.

EXAMPLE B Antipsychotic Activity: Study of Antagonism of Amphetamine-Induced Hyperactivity

The selective antagonism of amphetamine-induced hyperactivity is regarded as an indicator of an antipsychotic activity.

PROTOCOL:

An injection by the IP route of 2 mg/kg of amphetamine induces a marked measurable hyperactivity. Sprague-Dawley rats weighing 200 to 250 g receive the compounds to be tested by the IP route before administration of the amphetamine and the amphetamine activity is then measured 30 minutes later for a period of 30 minutes. 12 animals are tested per dose. Reference: Costall B. et al.--Brain Res., 123: 89-111.

RESULTS:

The compounds of the invention very significantly inhibit amphetamine-induced hyperactivity.

EXAMPLE C Measurement of Anxiolytic Activity: Light/Dark Cage Test

Rats prefer enclosed and dark spaces to open and illuminated spaces. This preference is reflected in the proportion of time spent in enclosed and dark spaces. A characteristic of anxiolytic compounds is to increase the time spent in open and illuminated spaces.

PROTOCOL:

The animals are placed in a cage consisting of 2 compartments, one being open and illuminated and the other being dark and enclosed. The time spent by the animal in each of the compartments, as well as the number of movements from one compartment to the other, is measured for a period of 5 minutes. 10 animals are studied per dose. Reference: Crawley J. N., Pharmacol. Biochem. Behav., 1981, vol 15, p 695-699.

RESULTS:

It clearly appears that the compounds of the invention have an anxiolytic activity since they increase very significantly the time spent by the animals in the illuminated compartment.

EXAMPLE D Analgesic Activity: Hotplate Test

Rats or mice are placed on a hotplate (58° C.) inside a Plexiglas® cylinder. The reaction time which the animal takes to lick its paws is measured. If no reaction is recorded, the test is terminated after 120 seconds. 10 animals are studied per dose. The tested compound is usually administered i.p. 30 minutes before the test.

16 mg.kg⁻¹ i.p. of morphine is used as the reference compound which inhibits the reaction time which the animals takes to lick its paws by 129%.

Reference: Eddy N. B., Liembach D., 1959. Synthetic Analgesics: II-dithienylbutenyl and dithienylbutylamines. J. Pharmacol. Exp. Ther., 107: 385-393.

Results: the compounds of the invention very significantly increase the reaction time which the animal takes to lick its paws. For example, 0.25 mg.kg⁻¹ of the compound of Example 48 inhibited this reaction time by 175%.

EXAMPLE E Mesaurement of the Toxicity

The toxicity was tested after oral administration of a 650 mg/kg dose to groups of 8 mice (26±2 grams). The animals are observed at regular intervals during the first day and daily during the 2 weeks following the treatment.

It appears that the compounds of the invention are not toxic at a dose of 650 mg/kg, and no disorder is generally observed after administration of such a dose.

EXAMPLE F Pharmaceutical Composition

Tablet containing a 2.5 mg dose of 3-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-6-(4-morpholinobutyl)benzothiazolin-2-one

    ______________________________________                                         Preparation for 1000 tablets:                                                  ______________________________________                                         2-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-                                                             2.5     g                                             6-(4-morpholinobutyl)benzothia-zolin-2-one                                     Wheat starch             15      g                                             Maize starch             15      g                                             Lactose                  65      g                                             Magnesium stearate       2       g                                             Silica                   1       g                                             Hydroxypropyl cellulose  2       g                                             ______________________________________                                     

We claim:
 1. A method of treating or preventing anxiety or depression in a mammal subject thereto, and depressive syndromes, psychotic conditions, and Parkinson's comprising the step of administering to said mammal an amount of a compound which is selected from those of formula (I): ##STR17## wherein: Ar represents phenyl or naphthyl, Ar being unsubstituted or substituted by one or more radicals selected from halogen, lower alkyl, lower alkoxy, and trifluoromethyl, n represents 0 or 1 to 4, inclusiveB represents ##STR18## and A represents a group of formula (A1) or (A2): ##STR19## wherein: E represents a linear or branched alkylene chain having 1 to 6 carbon atoms, inclusive, R₁ represents a radical selected from hydrogen, hydroxyl, lower alkyl, and lower alkoxy, R₂ represents ##STR20## where E₁ has the same definition as E as described above and where R₄ and R₅ are selected, independently from one another, from hydrogen and lower alkyl, or form, together with the nitrogen to which attached, a heterocycle selected from pyrrolidine, piperidine, substituted piperidine, morpholine, piperazine, and substituted piperazine, R₃ represents a radical selected from hydrogen and lower alkyl, and X represents sulfur or oxygen, its optical isomers, in pure form or in the form of a mixture, and addition salts thereof with a pharmaceutically-acceptable base or acid,it being understood that, except when otherwise specified, the terms "lower alkyl" and "lower alkoxy" denote linear or branched groups having 1 to 6 carbon atoms, inclusive, and the term "substituted" assumed by the "piperidine" and "piperazine" heterocycles means that these heterocycles can be substituted in the 4-position by a radical selected from lower alkyl, aryl, and lower arylalkyl, the term "aryl" denoting phenyl, naphthyl, or pyridyl, which aryl can itself be unsubstituted or substituted by one or more radicals selected from halogen, lower alkyl, hydroxyl, lower alkoxy, and trifluoromethyl, which is effective for said purpose.
 2. A method as claimed in claim 1, wherein Ar represents 4-fluorophenyl.
 3. A method as claimed in claim 1, wherein Ar represents 4-fluorophenyl, n is zero andB represents --CH<.
 4. A method as claimed in claim 1, wherein R₂ represents 4-morpholinobutyl.
 5. A method as claimed in claim 1, wherein the compound is selected from 3-{2-[4-(4-fluorobenzyl)piperidino]ethyl}-6-{4-[4-(3-trifluoromethylphenyl)piperazinyl]butyl}benzothiazolin-2-one and addition salts thereof with a pharmaceutically-acceptable acid.
 6. A method as claimed in claim 1, wherein the compound is selected from 3-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-6-(4morpholinobutyl)benzothiazon-2-one and addition salts there of with a pharmaceutically-acceptable acid.
 7. A method of claim 1, wherein the compound is administered in the form of a pharmaceutical composition containing the compound in combination with one or more pharmaceutically-acceptable excipients or carriers.
 8. A method of as claimed in 1, wherein the compound is selected from 3-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-6-{4-[4-(2-methoxy-phenyl)piperazinyl]butyl}benzothiazolin-2-one and addition salts thereof with a pharmaceutically-acceptable acid.
 9. A method as claimed in claim 1, wherein the compound is selected from 3-[2-[4-(4-fluorobenzyl)piperidino]ethyl]-6-{4-[4-(2-methoxyphenyl)-piperazinyl]butyl}benzothiazolin-2-one and addition salts thereof with a pharmaceutically-acceptable acid. 